Macrophage actin-associated and tyrosine phosphorylated protein (MAYP), also known as praline- serinethreonine phosphatase-interacting protein 2 (PSTPIP2), belongs to the Pombe Cdc15 homology (PCH) family of proteins that has been shown to coordinate membrane and cytoskeletal dynamics. MAYP is selectively expressed in macrophages, mast cells and osteoclasts and is an actin-bundling protein that regulates filopodia formation and macrophage motililty. PCH proteins play important roles in immunity by regulating the cell surface expression of Fas ligand and cytokine production. Two different mouse MAYP missense mutations, resulting in no (cmo) or low (Lupo) MAYP expression, lead to a psoriatic arthritis-like autoinflammatory disease characterized by ear and paw necrosis, cartilage and bone destruction, indicating that MAYP has an anti-inflammatory activity. The inflammatory diseases in both MAYP mutant mice are mediated by macrophages, which exhibit increased secretion of inflammatory mediators, in particular, Galectin-3 and MIP-1a, without an elevation in their mRNA levels, indicating that MAYP negatively regulates inflammatory mediator release at the post-transcriptional level. MAYP interacts with Galectin-3 and exocytic proteins, providing hypotheses to test concerning its mechanism of action. MAYP mutant macrophages also have decreased phagocytic capacity which may result in their failing to efficiently clear apoptotic bodies, cell debris or pathogens from injured tissue. Our overall hypothesis is that MAYP autoinflammatory disease is due to MAYP deficiency which leads to increased production of inflammatory mediators by macrophages and that disease is further enhanced by macrophage phagocytic defects. The overall aim of this proposal is to establish the molecular basis of MAYP action in regulating macrophage activation.
The specific aims are to: 1. Elucidate the mechanism of action of MAYP in regulating Gal-3 and MIP-1 a secretion by macrophages. 2. Establish the mechanism by which MAYP deficiency impairs phagocytosis. 3. Determine and utilize the three dimensional structure of MAYP to identify functionally important regions. The proposed experiments will contribute to an understanding of the molecular mechanisms involved in skin inflammation and joint and bone destruction in psoriasis, arthritis and related autoinflammatory disorders. In addition, they will provide a better understanding of the action of PCH proteins in controlling the inflammatory response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AR054486-02
Application #
7603124
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Mancini, Marie
Project Start
2008-04-04
Project End
2013-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
2
Fiscal Year
2009
Total Cost
$129,735
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Chitu, Violeta; Stanley, E Richard (2015) PACSIN2: a BAR-rier forming the megakaryocyte DMS. Blood 126:5-6
Stanley, E Richard; Chitu, Violeta (2014) CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol 6:
Chitu, Violeta; Nacu, Viorel; Charles, Julia F et al. (2012) PSTPIP2 deficiency in mice causes osteopenia and increased differentiation of multipotent myeloid precursors into osteoclasts. Blood 120:3126-35
Chitu, Violeta; Yeung, Yee-Guide; Yu, Wenfeng et al. (2011) Measurement of macrophage growth and differentiation. Curr Protoc Immunol Chapter 14:Unit 14.20.1-26
Zhang, Shengnan; Chitu, Violeta; Stanley, E Richard et al. (2011) Fes tyrosine kinase expression in the tumor niche correlates with enhanced tumor growth, angiogenesis, circulating tumor cells, metastasis, and infiltrating macrophages. Cancer Res 71:1465-73
Wei, Suwen; Nandi, Sayan; Chitu, Violeta et al. (2010) Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. J Leukoc Biol 88:495-505
Kara, Firas M; Chitu, Violeta; Sloane, Jennifer et al. (2010) Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function. FASEB J 24:2325-33
Chitu, Violeta; Ferguson, Polly J; de Bruijn, Rosalie et al. (2009) Primed innate immunity leads to autoinflammatory disease in PSTPIP2-deficient cmo mice. Blood 114:2497-505